The objective of this research proposal is to further our understanding of T cell development and T cell function in health and disease. To this end we will use methods of molecular biology (cloning, polymerase chain reaction aided analytical methods, chromosome walking, site directed mutagenesis, gene transfection for transient and stable expression, gel retardation assays, construction of transgenic mice and of mutant mice using the ES cell homologous integration technique) as well as cell and thymus organ culture techniques, cell fusion techniques, flow cytometry, immunohistology and various in vivo assay for T cell functions (skin grafting, ear assay for delayed type hypersensitivity). We will study the molecular mechanism of the initial steps of alpha/beta and gamma/delta T cell differentiation, gamma/delta TCR repertoire generation, positive and negative selection alpha/beta and gamma/delta T cells in the thymus and the homing of gamma/delta T cell subsets to different epithelia. We will analyse TL and CD1 genes and the putative role of their products as antigen presenting proteins for gamma/delta T cells and investigate the molecular details and the putative biological significance of heat shock protein recognition by gamma/delta T cells. A major effort will be made to elucidate the in vivo function of gamma/delta T cells in lymphocyte development, in various immune responses (antibody responses, DTH responses, graft rejection) as well as in infectious diseases, auto immune diseases and tumor immunity.